Project Summary The proposed technologies effectively address a significant shortcoming in current MRI protocols, that is the incapability of existing protocols to acquire a complete set of high-resolution, artifact-free, multi- contrast and quantitative MR images from challenging patients (e.g., Parkinson?s disease (PD) patients; stroke patients; pediatric populations) within clinically-feasible time. Here we will develop and integrate multidisciplinary approaches to maximize the translatability of advanced MRI technologies to clinical uses for challenging patients. Aim 1A) We will incorporate fast scan strategies, motion-correction and distortion- correction modules into our recently developed multiplexed sensitivity encoded (MUSE) DTI and fMRI in a novel way, to enable high-resolution connectivity mapping (at 0.85 mm isotropic resolution, in contrast to 1.5mm to 4mm that are standard with conventional DTI and fMRI protocols). At this resolution, critical network nodes (e.g., motor and non-motor subregions of subthalamic nucleus (STN)) and pathways that are important for patient care (e.g., improved MRI guidance for deep brain stimulation) can be much more reliably resolved. Aim 1B) We will develop an innovative multi-echo-pathway MRI method to significantly reduce the scan time of multi-contrast MRI and parametric imaging (e.g., achieving simultaneous T1 and T2 parametric mapping within 3 min: ~ 4-fold improvement than conventional protocols). Aim 1C) We will develop motion artifact correction schemes that are suitable for high-resolution multi-contrast MRI in challenging patients. Aim 2A) We plan to first evaluate the MRI technologies in healthy adult volunteers in two ways. First, data obtained with our methods and conventional, more time-consuming protocols will be quantitatively compared. Second, new knowledge that can only be produced from our high-resolution data (e.g., imaging motor- subregions of STN) will be confirmed with theta-burst transcranial magnetic simulation (TMS) neuro- modulation of motor networks. Aim 2B) We plan to evaluate the proposed imaging technologies in PD patients in three ways. First, in a cross-sectional study, we will acquire and compare imaging data from 1) those who are at high risk of PD conversion (with positive family history, hyposmia, rapid eye movement sleep behavior disorder, constipation, and impairments in instrumental daily activities), 2) early-stage PD patients (Hoehn and Yahr scale 1 and 2), and 3) advanced-stage PD patients (Hoehn and Yahr scale 3 and 4). Difference in brain structure and function across three populations will be assessed. Second, in a longitudinal study, imaging data obtained from subjects with high risk of conversion to PD in year 2 and year 5 of the project will be compared to measure prodromal brain signal abnormalities and their correlation with longitudinal behavioral and MRI signal changes. Third, we will compare imaging data obtained from PD patients and non-PD patients (mainly essential tremor) to evaluate the differential diagnosis accuracy of the proposed imaging technologies.